Members of the cadherin family of cell-cell adhesion molecules are well-established players in tumor progression, but the importance of the desmosomal cadherin sub-class is poorly understood. Of particular interest is the desmoglein (Dsg) subfamily, three of which are distributed in distinct patterns within the self-renewing, complex epithelia of the oral cavity. Our overarching hypothesis is that Dsgs regulate homeostasis by sustaining proliferation in the basal layer while promoting differentiation as cells stratify, and that alterations occurring during tumor progression upset this balance. This proposal focuses on desmoglein 1 (Dsg1), which, among cadherins tested, was uniquely associated with poor patient outcome in head and neck squamous cell carcinoma (HNSCC). Dsg1 is expressed as cells emerge from the basal layer to differentiate and form a protective barrier. We showed that Dsg1 actively participates in epithelial morphogenesis by promoting a differentiation program in epidermal keratinocytes, via suppression of ErbB/MAPK signaling. Importantly, over 90% of HNSCC express elevated ErbB1. We hypothesize that Dsg1 regulates homeostasis in HNSCC by promoting differentiation while limiting tumor progression through an interaction with the ErbB binding protein ERBIN, and that bi-directional interactions between Dsgs and membrane bound sheddases in the ADAM family further regulate tumor cell fate. Our aims are to: 1) test the hypothesis that Dsg1 promotes a program of HNSCC differentiation, to test whether this occurs by attenuating MAPK signaling, and to determine whether Dsg1 loss is associated with suppressed differentiation and increased proliferation/invasion in an animal model and human HNSCCs, 2) determine whether the scaffolding protein, ERBIN, mediates Dsg1-dependent signaling in vitro and in vivo by interfering with a Ras/Raf/Shoc2 complex, and 3) test the hypothesis that Dsgs are both substrates and inhibitors of ADAM sheddase activity and determine the impact of this bi-directional relationship on Dsg-dependent adhesion and signaling in vitro, and tumor progression in vivo. Knowledge gained from this study holds promise for the design of innovative therapies including those that circumvent resistance to drugs targeting upstream players in the ErbB/MAPK pathway.